Dual-Acting Compounds Targeting Endocannabinoid and Endovanilloid Systems-A Novel Treatment Option for Chronic Pain Management.

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“Compared with acute pain that arises suddenly in response to a specific injury and is usually treatable, chronic pain persists over time, and is often resistant to medical treatment.

Because of the heterogeneity of chronic pain origins, satisfactory therapies for its treatment are lacking, leading to an urgent need for the development of new treatments.

The leading approach in drug design is selective compounds, though they are often less effective and require chronic dosing with many side effects.

Herein, we review novel approaches to drug design for the treatment of chronic pain represented by dual-acting compounds, which operate at more than one biological target.

A number of studies suggest the involvement of the cannabinoid and vanilloid receptors in pain.

Interestingly cannabinoid system is in interrelation with other systems that comprise lipid mediators: prostaglandins, produced by COX enzyme.

Therefore, in the present review, we summarize the role of dual-acting molecules (FAAH/TRPV1 and FAAH/COX-2 inhibitors) that interact with endocannabinoid and endovanillinoid systems and act as analgesics by elevating the endogenously produced endocannabinoids and dampening the production of pro-inflammatory prostaglandins.

The plasticity of the endocannabinoid system (ECS) and the ability of a single chemical entity to exert an activity on two receptor systems has been developed and extensively investigated.

Here, we review up-to-date pharmacological studies on compounds interacting with FAAH enzyme together with TRPV1 receptor or COX-2 enzyme respectively.

Multi-target pharmacological intervention for treating pain may lead to the development of original and efficient treatments.”

http://www.ncbi.nlm.nih.gov/pubmed/27582708

The Influence of the CB1 Receptor Ligands on the Schizophrenia-Like Effects in Mice Induced by MK-801.

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“A growing body of psychiatric research has emerged, focusing on the role of endocannabinoid system in psychiatric disorders.

For example, the endocannabinoid system, via cannabinoid CB (CB1 and CB2) receptors, is able to control the function of many receptors, such as N-methyl-D-aspartate (NMDA) receptors connected strictly with psychosis or other schizophrenia-associated symptoms.

The aim of the present research was to investigate the impact of the CB1 receptor ligands on the symptoms typical for schizophrenia.

The present findings confirm that endocannabinoid system is able to modify a variety of schizophrenia-like responses, including the cognitive disturbances and hyperlocomotion in mice.

Antipsychotic-like effects induced by CB1 receptor antagonist, obtained in our research, confirm the potential effect of CB1 receptor blockade and could have important therapeutic implications on clinical settings, in the future.”

http://www.ncbi.nlm.nih.gov/pubmed/27577742

Efficacy and Safety of Cannabidiol and Tetrahydrocannabivarin on Glycemic and Lipid Parameters in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Pilot Study.

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“Cannabidiol (CBD) and Δ9-tetrahydrocannabivarin (THCV) are nonpsychoactive phytocannabinoids affecting lipid and glucose metabolism in animal models. This study set out to examine the effects of these compounds in patients with type 2 diabetes.

RESULTS:

Compared with placebo, THCV significantly decreased fasting plasma glucose (estimated treatment difference [ETD] = -1.2 mmol/L; P < 0.05) and improved pancreatic β-cell function (HOMA2 β-cell function [ETD = -44.51 points; P < 0.01]), adiponectin (ETD = -5.9 × 106 pg/mL; P < 0.01), and apolipoprotein A (ETD = -6.02 μmol/L; P < 0.05), although plasma HDL was unaffected. Compared with baseline (but not placebo), CBD decreased resistin (-898 pg/ml; P < 0.05) and increased glucose-dependent insulinotropic peptide (21.9 pg/ml; P < 0.05). None of the combination treatments had a significant impact on end points. CBD and THCV were well tolerated.

CONCLUSIONS:

THCV could represent a new therapeutic agent in glycemic control in subjects with type 2 diabetes.”

http://www.ncbi.nlm.nih.gov/pubmed/27573936

Marijuana use in adults admitted to a Canadian epilepsy monitoring unit.

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“Epidemiologic evidence supporting antiseizure properties of cannabis is limited and controversial.

We determined the prevalence of marijuana use and its perceived effects in patients with and without epilepsy.

Patients with uncontrolled epilepsy or nonepileptic events had a high rate of marijuana use with associated perceived improvements in seizure control, stress, sleep, and drug side effects.

Stress reduction may contribute to the perceived impact of marijuana on seizures and nonepileptic events in adults.”

http://www.ncbi.nlm.nih.gov/pubmed/27568641

Cannabinoid 2 receptor is a novel anti-inflammatory target in experimental proliferative vitreoretinopathy.

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“Proliferative vitreoretinopathy (PVR) can develop after ocular trauma or inflammation and is a common complication of surgery to correct retinal detachment.

Currently, there are no pharmacological treatments for PVR.

Cannabinoids acting at cannabinoid 2 receptor (CB2R) can decrease inflammation and fibrosis.

The objective of this study was to examine the anti-inflammatory actions of CB2R as a candidate novel therapeutic target in experimental PVR.

In conclusion, our results indicate that intervention at early stage PVR with CB2R agonists reduces ocular inflammation and disease severity.

CB2R may represent a therapeutic target to prevent PVR progression and vision loss.”

http://www.ncbi.nlm.nih.gov/pubmed/27569993

Delineating the Efficacy of a Cannabis-Based Medicine at Advanced Stages of Dementia in a Murine Model.

 

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“Previous reports have demonstrated that the combination of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) botanical extracts, which are the components of an already approved cannabis-based medicine, reduce the Alzheimer-like phenotype of AβPP/PS1 transgenic mice when chronically administered during the early symptomatic stage.

Here, we provide evidence that such natural cannabinoids are still effective in reducing memory impairment in AβPP/PS1 mice at advanced stages of the disease but are not effective in modifying the Aβ processing or in reducing the glial reactivity associated with aberrant Aβ deposition as occurs when administered at early stages of the disease.

The present study also demonstrates that natural cannabinoids do not affect cognitive impairment associated with healthy aging in wild-type mice.

The positive effects induced by Δ9-THC and CBD in aged AβPP/PS1 mice are associated with reduced GluR2/3 and increased levels of GABA-A Ra1 in cannabinoid-treated animals when compared with animals treated with vehicle alone.”

http://www.ncbi.nlm.nih.gov/pubmed/27567873

Endocannabinoids inhibit neurogenic inflammation in murine joints by a non-canonical cannabinoid receptor mechanism.

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“Neurogenic inflammation is a local inflammatory response that is driven by the peripheral release of neuropeptides from small diameter afferents which occurs in many organs including joints.

The knee joint has a rich endocannabinoid system which has been shown to decrease acute synovitis.

The aim of this study was to investigate the influence of joint afferents on leukocyte-endothelial interactions within the synovial microcirculation of mice and determine the role of endocannabinoids on this inflammatory response.

These results provide evidence that antidromic stimulation of the mouse saphenous nerve promotes leukocyte rolling within the synovial microcirculation, and that endocannabinoids can attenuate this neurogenic inflammatory response.”

http://www.ncbi.nlm.nih.gov/pubmed/27567396

Activation of type 1 cannabinoid receptor (CB1R) promotes neurogenesis in murine subventricular zone cell cultures.

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“The endocannabinoid system has been implicated in the modulation of adult neurogenesis.

Here, we describe the effect of type 1 cannabinoid receptor (CB1R) activation on self-renewal, proliferation and neuronal differentiation in mouse neonatal subventricular zone (SVZ) stem/progenitor cell cultures.

There is an emerging consensus that endocannabinoid signaling plays a major role in adult neurogenesis.

Cannabinoids act on at least two types of receptors, the type 1 and type 2 cannabinoid receptors (CB1R and CB2R), which are, respectively, predominantly distributed in the central nervous system (CNS) and immune system, although some studies have described the presence of low levels of CB2R in the brain.

Taken together, these results demonstrate that CB1R activation induces proliferation, self-renewal and neuronal differentiation from mouse neonatal SVZ cell cultures.

 Collectively, CB1R agonists render neurons less excitable and thus promote neuroprotection.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660454/

The gastrointestinal tract – a central organ of cannabinoid signaling in health and disease.

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“In ancient medicine, extracts of the marijuana plant Cannabis sativa were used against diseases of the gastrointestinal (GI) tract.

Today, our knowledge of the ingredients of the Cannabis plant has remarkably advanced enabling us to use a variety of herbal and synthetic cannabinoid (CB) compounds to study the endocannabinoid system (ECS), a physiologic entity that controls tissue homeostasis with the help of endogenously produced CBs and their receptors.

After many anecdotal reports suggested beneficial effects of Cannabis in GI disorders, it was not surprising to discover that the GI tract accommodates and expresses all the components of the ECS.

Cannabinoid receptors and their endogenous ligands, the endocannabinoids, participate in the regulation of GI motility, secretion, and the maintenance of the epithelial barrier integrity.

In addition, other receptors, such as the transient receptor potential cation channel subfamily V member 1 (TRPV1), the peroxisome proliferator-activated receptor alpha (PPARα) and the G-protein coupled receptor 55 (GPR55), are important participants in the actions of CBs in the gut and critically determine the course of bowel inflammation and colon cancer.

PURPOSE:

The following review summarizes important and recent findings on the role of CB receptors and their ligands in the GI tract with emphasis on GI disorders, such as irritable bowel syndrome, inflammatory bowel disease, and colon cancer.”

http://www.ncbi.nlm.nih.gov/pubmed/27561826